Non-melanoma skin cancer (NMSC) has the highest incidence of all cancers in the United States. While rarely fatal, the treatment of NMSC is estimated to cost our healthcare system over a billion dollars annually. Therefore, the prevention rather than the excision of NMSC has the potential to have a major impact on healthcare costs. While it is clear that exposure to the ultraviolet components in sunlight (specifically UVB) can initiate and promote the development of NMSC, the reasons why some individuals develop skin cancer and survival of keratinocytes at the cost of replicative potential, i.e. keratinocytes become senescent. Absence of IGF-1 receptor activation, keratinocytes are more sensitive to UVB-induced apoptosis, but the keratinocytes that do survive retain the capacity to proliferate, an inappropriate UVB response. In vivo, we have demonstrated that keratinocytes in young skin respond appropriately to UVB exposure; however, a surprisingly high percentage of keratinocytes in geriatric skin respond inappropriately to UVB irradiation. We hypothesize that this inappropriate response to UVB irradiation in geriatric skin could lead to initiated carcinogenic keratinocytes. Furthermore, the inappropriate UVB response in geriatric keratinocytes is due to the silencing of IGF-1 expression (and corresponding inactivation of the IGF-1 receptor) in geriatric skin. Finally, we have shown that treatment of geriatric skin with ablative dermal rejuvenation therapies can re- establish youthful IGF-1 levels and subsequently reinstate the appropriate UVB response on sun-protected skin. In this proposal, we will expand our studies linking the susceptibility of geriatric skin to UVB-induced cancer to the IGF-1/IGF-1R signaling pathway. Although skin cancer can occur at any age, there is a strong correlation between the development of skin cancer and advancing age. In fact, the majority of skin cancers are found in people over the age of 60; therefore, age is also a risk factor for the development of skin cancer. Using data derived from recent in vitro, in vivo, and epidemiological data, we have demonstrated that aberrations in insulin-like growth factor-1 (IGF-1)/IGF-1 receptor signaling in geriatric skin contributes to their enhanced susceptibility to develop NMSC. In vitro, activation of the IGF-1 receptor regulates the response of normal human keratinocytes to UVB irradiation others do not are not fully understood. The IGF-1 receptor-dependent UVB response results in enhanced In the First, we will determine whether dermal rejuvenation therapies on geriatric skin will increase IGF-1 levels and correct the inappropriate UVB response for extended periods of time. Second, using human skin grafted onto immunodeficient mice we will mechanistically link the IGF-1 receptor-dependent inappropriate response to increased development of actinic neoplasia. Finally, mechanistic studies will examine elements of the IGF-1R signaling pathway in keratinocytes using UVB- irradiated human skin in vitro and in vivo. The successful completion of these specific aims will provide a direct link between the inappropriate UVB response in geriatric skin and the development of NMSC in geriatric patients. Furthermore, we will continue to evaluate the utility of prophylactic therapies that can prevent the occurrence of aging-associated photocarcinogenesis. PUBLIC HEALTH RELEVANCE: While investigating why the risk of non-melanoma skin cancer rises abruptly after the age of 50, we have previously demonstrated that geriatric individuals have an enhanced susceptibility to incur DNA damage following ultraviolet light exposure which is dependent on alterations in the IGF-1/IGF-1R signal transduction pathway. Furthermore, studies using dermal rejuvenation techniques indicate that this inappropriate response to ultraviolet light can be corrected in geriatric patients. The results of experiments in this proposl will allow us to determine how long the benefits from dermal rejuvenation are sustained and define mechanisms how the inappropriate response to ultraviolet light by geriatric individuals leads to the development of non-melanoma skin cancer.